Mutations in Igα (CD79a) result in in B-cell development

Mutations in Btk, mu heavy chain, or the surrogate light chain account for 85-90% of patients with early onset hypogammaglobulinemia and absent B cells. The nature of the defect in the remaining patients is unknown. We screened 25 such patients for mutations in genes encoding components of the pre-B-cell receptor (pre-BCR) complex. A 2-year-old girl was found to have a homozygous splice defect in Ig alpha, a transmembrane protein that forms part of the Ig alpha/Ig beta signal-transduction module of the pre-BCR. Studies in mice suggest that the Ig beta component of the pre-BCR influences V-DJ rearrangement before cell-surface expression of mu heavy chain. To determine whether Ig alpha plays a similar role, we compared B-cell development in an Ig alpha-deficient patient with that seen in a mu heavy chain-deficient patient. By immunofluorescence, both patients had a complete block in B-cell development at the pro-B to pre-B transition; both patients also had an equivalent number and diversity of rearranged V-DJ sequences. These results indicate that mutations in Ig alpha can be a cause of agammaglobulinemia. Furthermore, they suggest that Ig alpha does not play a critical role in B-cell development until it is expressed, along with mu heavy chain, as part of the pre-BCR.